1. Field of the Invention
This invention relates to methods, formulations, and apparatus that allow fluid and less-than-solid pharmaceutical formulations to be applied onto certain human body surfaces and then be converted into a more solid state, thereby facilitating administration and removal of the formulation after application.
This invention also relates to methods and formulations that can anesthetize the skin or certain compromised human body surfaces and proximate tissues, such as skin having an abrasion, laceration, or post-surgery wound. More specifically, the present invention relates to less-than-solid anesthetic formulations and delivery systems that can be applied to the skin or compromised surfaces and subsequently converted to a soft coherent solid state and then peeled off the after the anesthetic effect is achieved.
In addition, this invention relates to applying formulations in which most of the local anesthetic agents are applied in an undissolved state onto a human body surface which is substantially lacking a barrier or layer of the skin, such as the stratum corneum, for obtaining more controlled and extended release of the local anesthetic agent(s).
2. Background of the Invention
Many medical formulations topically applied onto human body surfaces are in the form of pastes, gels, ointments, cream, solutions similar less than solid states that are vulnerable to being wiped off inadvertently or flowing away from the application site. For example, after a solution formulation is applied onto human skin, it can flow away quickly and thus result in a short contact time with the original application site. After a cream is applied onto the skin of an arm, it can be rubbed off in the daily activities if not protected by a cover. If a minoxidil cream or solution is applied onto the scalp for promoting hair growth before sleeping, it can be rubbed off on the pillow overnight. In addition, many xe2x80x9cless-than-solidxe2x80x9d formulations are messy and take an effort to remove.
Topical delivery of anesthesia is a good example of how prior art delivery methods and formulations are limited. Medical procedures on the skin are often painful. Most people are familiar with the pain and discomfort associated with minor procedures on the skin, such as receiving stitches or having a mole removed. Patients undergoing these procedures appreciate the benefits of fast and effective anesthesia. Even recently developed cosmetic procedures, such as laser resurfacing of skin and laser removal of port wine stain or similar birth marks, require significant anesthesia. Cosmetic procedures on facial skin can be especially painful. Currently, several prior art methods may be used to anesthetize the skin before administering these medical and cosmetic procedures, including general anesthesia or regional nerve block by injection, local anesthesia delivered by injection, and local anesthesia delivered topically, such as applying a eutectic mixture of local anesthetic cream (EMLA cream) onto the skin.
Prior art methods for anesthetizing skin have serious drawbacks. General anesthesia or regional nerve block by injection usually requires the involvement of an anesthesiologist and typically cannot be performed in a private practice setting. Injection of local anesthetic is painful, invasive, and may change the shape of the skin surface. It will also leave needle holes in the skin and may scab or scar. The disadvantages of needle injection may be especially unacceptable when the anesthesia is to be delivered to the facial tissues. While the use of EMLA cream is noninvasive, the onset time is often too long. Additionally, EMLA cream needs to be covered with an occlusion membrane while waiting for the anesthetic effect and EMLA cream leaves a mess on the skin which needs to be removed after the anesthetic is delivered.
Just as patients benefit from effective anesthetizing of the skin for certain medical and cosmetic procedures, patients experiencing discomfort as the result of compromised human body surfaces and the procedures associated with treating compromised surfaces can also benefit from convenient local anesthesia. Patients with open wounds, such as abrasions, lacerations, or ulcers may require anesthesia to control pain and to cleanse or close the wound. Chronic ulcer surfaces, surfaces that have scabs and dead tissues (i.e. recovering burn wound), need to be debrided from time to time.
Debridement is a painful procedure if anesthesia is not provided. General analgesia, intravenous narcotic analgesics, regional nerve block by injection, and epidural anesthesia may be used to control the pain associated with debridement or wounds. However, delivery of a general analgesic, regional nerve block by injection, epidural, or intravenous analgesic typically requires specially trained medical personnel and/or special medical equipment to administer. The procedures also expose patients to significant risks and expose care givers to significant liability. Applying analgesic formulation in which most of the active drug is dissolved onto skin lacking stratum corneum may result in dangerously rapid absorption of the drug and short duration of the effect.
Some local anesthetic agents used in the prior art formulations and apparatus of this invention to noninvasively anesthetize or provide analgesia to human body surfaces and tissues under the surface have significant limitations. Some commonly used local anesthetics, such as lidocaine have relatively limited penetration and sustain the analgesic effect for a relatively short period of time.
Thus, it would be advantageous to develop methods in which the formulation is in the less-than solid form, such as a paste, gel, ointment, cream or solution, before being applied onto a human body surface and then the formulation can be converted into a coherent, solidified gel by a certain mechanism during the application to facilitate removal. For some medications, it would also be advantageous if the means for converting the formulation into a coherent solid also included an occlusive cover that inhibited the evaporation of the solvent in the formulation and prevented the formulation from being rubbed off.
It would be particularly advantageous to develop methods and formulations to conveniently and noninvasively anesthetize the skin, especially the facial skin. It would also be advantageous to develop methods and formulations to more conveniently and safely anesthetize compromised human body surfaces. It would further be an advantage to develop an anesthetic formulation that can delivery anesthetic quickly and transdermally and that can be removed easily.
In this application, the phrase xe2x80x9cless-than-solid phase,xe2x80x9d xe2x80x9cless-than-solid state,xe2x80x9d or xe2x80x9cless-than-solid formxe2x80x9d means, unless specifically described otherwise, a form that is not as hard and as coherent as a solidified gel. Examples of such xe2x80x9cless-than-solidxe2x80x9d substances include toothpaste, cream, ointment, etc. One common property of these xe2x80x9cless-than-solidxe2x80x9d substances is that the substance is not strongly cohesive, or in other words, the substance is a liquid or a highly viscous fluid. In practical terms, a xe2x80x9cless-than-solidxe2x80x9d substance is a substance that one cannot grab and lift as a cohesive whole.
The present invention is directed toward a method and device for dermal delivery of a drug formulation. More specifically, the invention is a method and device for delivering a topically delivered drug using a formulation which is applied to a patient""s skin as a fluid, moldable, or less-than-solid drug formulation, but which can be subsequently converted to a coherent, soft solid phase to facilitate removal of the formulation.
The formulation generally comprises a topically delivered drug, a conversion agent, and a vehicle medium or carrier. The drug is dispersed in the carrier. The conversion agent may be included in the drug formulation with the vehicle medium (carrier) and the drug or may be added following the application of the formulation. At the time of application of the formulation to the skin, the formulation is in a less-than-solid phase. At the conclusion of the treatment, the formulation is a coherent, soft solid that can be cleanly peeled from the skin.
The topically delivered drug or pharmaceutical can be a single drug, such as a single local anesthetic, or a combination of drugs, such as a eutectic mixture of lidocaine and tetracaine. The drug may be dispersed throughout the formulation in a solid form, dissolved in oil droplets which are dispersed in the vehicle medium, or in aqueous solution within the vehicle medium. The drug should be capable of transdermal delivery and have a permeability rate which allows controlled and effective delivery of the drug using the present invention. Alternatively, the drug may have a permeability rate which can be enhanced so as to be effective with the present invention, such as with permeation enhancers.
The vehicle medium may be one or more pharmaceutical excipients known in the art. The vehicle medium may also provide a stable environment for the drug. For example, the vehicle medium may contain buffers to maintain an appropriate pH or may contain agents to reduce hydrolytic reactions among the ingredients of the formulation. The vehicle medium also facilitates the application of the formulation. Ingredients which allow the formulation to maintain a desired viscosity during application can make applying the formulation easier. The vehicle medium will also facilitate delivery of the drug. Permeation enhancers can be included in the vehicle medium to increase the absorption rate of the drug. The vehicle medium may also aid in the removal of the formulation after delivery. Specifically, the vehicle medium may contain ingredients such as emulsifying agents, plasticizers, viscosity agents, and hygroscopic agents.
The conversion agent provides the formulation with the ability to change from one phase to another more solid and coherent phase, such as from a liquid or cream to a soft solid. The formulation is applied to a patient""s skin in such a way as to form a continuous layer of formulation. (Naturally, the formulation can be applied to different areas of a patient""s skin to form several, different xe2x80x9ccontinuous layers.xe2x80x9d) When the phase change occurs, the solidified formulation is more easily removed from the patient""s skin. The formulation does not leave behind residues or films. It is possible that in some circumstances many formulations in the forms of gel, cream, or paste can be dried to yield a solid. However, A unique feature of the formulation in this invention is that the solid phase (which is converted from the original less-than-solid formulation) is coherent and has a certain strength so it can be peeled off the body surface as a layer, leaving little residual formulation. The formulation in solid form will also be flexible and not brittle.
For some formulations, the phase change may be passively triggered. Passive initiation of the phase change can be the result of a change in environment as the formulation is taken out of storage and is applied to the skin of the patient. Passive initiation does not require the patient or caregiver to actively begin the formulation""s conversion process; the conversion process is initiated by some naturally occurring condition. For example, a phase change that is passively initiated occurs when the water content of the formulation changes due to evaporation to the atmosphere and the remaining pharmaceutical ingredients may comprise a gelling agent which allows the formulation to convert to a soft, coherent solid or gel. If polyvinyl alcohol is an ingredient in a cream formulation of the present invention, the polyvinyl alcohol can act as a conversion agent and transform the cream formulation into a solid as the formulation loses water to the atmosphere through evaporation. Other potential environmental triggers which can initiate a passive phase change include, but are not limited to, exposing the formulation to human body surface temperature and/or exposing the formulation to air or to light. These passive triggers can also act as a safety mechanism to help prevent over dosing.
Another mechanism for converting a liquid, paste, or cream formulation into a coherent, solidified gel involves the use of thermally reversible gel polymers (a xe2x80x9cthermal gelxe2x80x9d), such as Pluronic F127 made by BASF Corporation, USA. A solution containing certain amount of thermal gel generally stays as a liquid at room temperature and becomes a non-fluid gel after the temperature is increased to a certain level. Some embodiments of this invention use thermal gel in liquid, paste, or cream pharmaceutical formulations. The formulation stays a viscous liquid, such as paste or cream, at room temperature. When the formulation is applied to human body surface, the body temperature causes the thermal gel to convert the formulation into a non-fluid gel. The non-fluid, xe2x80x9cnon-flowablexe2x80x9d gel has advantages over the original form of the formulation because the non-fluid gel is harder to rub off, do not flow away from the application site and yet can still be removed easily.
In order to achieve the conversion to the non-fluid gel on a human body surface, the conversion temperature may need to be optimized by specially designing the chemical structure and/or components of the thermal gel polymer. For example, thermal gels designed to be used in injectable formulations such as are found in the prior art may have a conversion temperature around 37xc2x0 C. However, the temperature of a topically applied formulation may only be increased to around 30xc2x0 C. by the skin. Therefore, in order for the conversion to occur on the skin, the conversion temperature must be around or below 30xc2x0 C. This may be achieved by changing the structure of the thermal gel polymer.
The conversion agent may additionally or alternatively be actively triggered. The patient or care-giver can activate the conversion agent either by actively changing the ambient environment around the formulation or by altering the chemical makeup of the formulation. The active initiation causes the formulation to change to a more solid phase. For example, solutions containing certain polymers undergo phase changes from liquid to solid form upon exposure to high levels of certain wavelengths of light. The patient or caregiver may actively initiate a phase change in the formulation by exposing a formulation containing such polymers to a high level of light having the appropriate corresponding wavelength. Similarly, the phase change can be actively initiated by adding a pharmaceutical ingredient to the formulation after removal from storage or after it is applied, such as applying a crosslinking agent to a formulation containing a crosslinkable ingredient. Formulations that allow the patient or caregiver to select when to initiate the phase change give additional control and flexibility over the drug delivery process, allowing the user to decide when to convert the formulation to gel (and thereby affect delivery of the drug) or to decide not to convert the formulation, if for some reason doing so is undesirable of unnecessary.
The method of the present invention comprises the first step of removing the formulation from its storage environment. The particular storage environment for each embodiment of the present invention may differ depending upon the nature of the formulation and the drug being used. For instance, a formulation may require a refrigerated storage environment that limits the exposure of the formulation to ambient temperature and/or air. Such an environment may be provided by storing the formulation in an air-tight container within a refrigerated compartment Other formulations may require limited exposure to light prior to administration. Some formulations will not require specialized storage environments.
After removing the formulation from the storage environment, the formulation is applied as a fluid, or other less-than-solid form, to a human body surface. The formulation may be molded or manipulated so that the surface being treated is covered by a substantially even layer of the formulation. A formulation applicator may be used to give the formulation layer a desired thickness. For certain drug formulations of the present invention, controlling the thickness of the formulation layer on the skin provides a measure of control over the delivery of the drug and over the time it takes for the drug formulation to complete its phase transition.
In view of the foregoing, the present invention provides a formulation, apparatus, and method for delivering a drug formulation that can be applied to and then peeled off a patient""s body surface after delivery of the drug. The formulation does not need to be rubbed or washed off the body surface. This approach to drug delivery through a patient""s body surface is safer because it is non-invasive and time controlled. The present invention can also save time by reducing the time required to clean up after application of the drug formulation.
The formulation and method of the present invention also allow the rate of the drug to be controlled. This can be especially important in applications which involve body surfaces that do not have a xe2x80x9cprotective barrierxe2x80x9d such as a layer of stratum corneum. Dermally delivered drugs which are applied to skin or a body surface which does not have a protective barrier can be rapidly absorbed and cause dangerously high rates of uptake. Furthermore, the drug can be absorbed too quickly so as to prevent the drug from having any extended therapeutic affect.